One-pot synthesis of 2-substituted benzo[b]furans via Pd-tetraphosphine catalyzed coupling of 2-halophenols with alkynes

Article abstract of DOI:10.1039/c4cc00815d

A catalyst composed of [Pd(η³-C₃H ₅)Cl]₂ and N,N,N',N'-tetra(diphenylphosphinomethyl) pyridine-2,6-diamine (L) was found to be effective for one-pot synthesis of 2-substituted benzo[b]furans from 2-halophenols and alkynes. For 2-bromo-3-hydroxypyridine, the catalyst loading could be as low as 1 ppm and the turnover number (TON) was up to 870000. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00815d

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One-pot synthesis of 2-substituted benzo[b]furans
via Pd–tetraphosphine catalyzed coupling of
2-halophenols with alkynes†
Cite this: Chem. Commun., 2014,
50, 6023
Received 30th January 2014,
Accepted 14th April 2014
Rong Zhou, Wei Wang, Zhi-jie Jiang, Kun Wang, Xue-li Zheng, Hai-yan Fu,
Hua Chen and Rui-xiang Li*
DOI: 10.1039/c4cc00815d
www.rsc.org/chemcomm
A catalyst composed of [Pd(g3-C3H5)Cl]2 and N,N,N’,N’-tetra(diphenyl-
phosphinomethyl)pyridine-2,6-diamine (L) was found to be effective for
one-pot synthesis of 2-substituted benzo[b]furans from 2-halophenols
and alkynes. For 2-bromo-3-hydroxypyridine, the catalyst loading
could be as low as 1 ppm and the turnover number (TON) was up to
870 000.
Table 1 Synthesis of 2-substituted benzo[b]furans using 2-iodophenol
and alkynesa
Entry
Alkyne
Time (h)
Product
Yield (%)
1
2
1
1
1
2
99
99
2-Substituted benzo[b]furan is a ubiquitous framework in natural
products and pharmaceuticals.1 Various methods have been developed
for the synthesis of benzo[b]furan derivatives. Pd-catalyzed one-pot
synthesis of benzo[b]furans from 2-halophenols and terminal alkynes
by a Sonogashira coupling–cyclization sequence is a classical, useful
and reliable way.2 Typically this reaction is performed using a
palladium phosphine catalyst in the presence of a copper salt as
a co-catalyst.2a,3 However, this reaction commonly employs
2-iodo-1a,4 or 2-bromophenols2a,f,3d,5 as substrates and there are a
few reports on the use of 2-chlorophenols.6 Recently, K. Manabe
found PdCl2(CH3CN)2/HTP (hydroxyterphenylphosphine) to be an
3
3
3
99
4
5
3
3
4
5
99
78
6
24
—
Trace
7
8
9
4
24
24
6
7
8
58
93
82
10
11
24
20
9
33
99
10
12
20
11
96
Scheme 1 Effect of the ligand on the reaction of 2-bromophenol and
phenylacetylene (r: L, K: PPh3, v: dppb, ’: no ligand, &: dppe,
m: P-Phos, 3: L1).
13
14
a
20
24
12
27
97
70b
Key Lab of Green Chemistry and Technology, Ministry of Education, Sichuan
University, Chengdu, China. E-mail: liruixiang@scu.edu.cn; Fax: +86-28-85412904
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc00815d
Conditions: 2-iodophenol 0.5 mmol, alkynes 0.6 mmol, DMF 2 mL, Cs2CO3
1 mmol, 130 1C, [Pd(Z3-C3H5)Cl]2 2.5 ꢀ 10ꢁ4 mmol, L 5 ꢀ 10ꢁ4 mmol,
isolated yield. b [Pd(Z3-C3H5)Cl]2 2.5 ꢀ 10ꢁ3 mmol, L 5 ꢀ 10ꢁ3 mmol.
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Table 2 Synthesis of benzo[b]furans using 2-bromophenols and alkynesa
effective catalyst for one-pot benzo[b]furan synthesis from
2-chlorophenols and alkynes, and then developed another
ligand DHTP (dihydroxyterphenylphosphine) to overcome the
drawbacks of the former system such as a long reaction time,
narrow substrate scope and the need for a sealed tube for the
reaction.6d But all of them required a high amount of palladium
(2–10 mol%). Therefore, the development of a simple and highly
efficient catalytic system is highly desired.
2-Bromo-
Time
(h)
Yield
Product (%)
Entry phenol
Alkyne
S/C
We previously reported the Pd–tetraphosphine (L) catalytic
system for Cu-free Sonogashira reaction, and found that aryl
bromides and even aryl chlorides were successfully alkynylated at
low palladium loading on water.7 In this respect, we applied this
catalyst to achieve the synthesis of 2-substituted benzo[b]furans.
Herein we present the palladium catalyzed one-pot synthesis
of 2-substituted benzo[b]furans from 2-halophenols and
alkynes using tetraphosphine L as the ligand. Firstly we tried
to obtain 2-substituted benzo[b]furan 1 using 2-bromophenol
and phenylacetylene as model reactants under the copper-free
conditions, and found that the catalyst [Pd(Z3-C3H5)Cl]2–L gave
the desired product in a yield of 99% (see the ESI,† Table S1). To
optimize conditions, the effect of various reaction parameters
(palladium precursor, base and solvent) on the outcome of the
reaction was explored. It was found that [Pd(Z3-C3H5)Cl]2 was the
most effective under otherwise identical conditions. Furthermore,
Cs2CO3 was much more effective than other bases. In our previous
work,7 water was the most effective solvent in copper-free Sonoga-
shira reaction, but it failed to give the product, and DMF was the
suitable solvent (Table S1, ESI,† entries 14–18). In order to explore
the role of the ligand, the relationship between conversions and
reaction time in different phosphine systems was investigated
(Scheme 1). It was found that in PPh3 or no ligand system, the
initial rate was much faster than in the ligand L system. But the rate
of reaction slowed down after 2 h due to the formation of palladium
black. In diphosphines and L1 systems, the increase of conversion
became very slow after 6 h. But the activity of the catalytic system
containing L was retained for the complete conversion of the
substrate obviously. Ligand L played a key role in this system
because it can maintain the stability of the palladium active species.
Under the optimized reaction conditions, 2-halophenols
and alkynes smoothly underwent transformation to produce
2-substituted benzo[b]furans in good to excellent yields. First,
the reactions of 2-iodophenol with various alkynes were tested
with a low palladium loading of 0.1 mol% (Table 1). With either
electron-rich or electron-poor aryl acetylenes as substrates,
2-iodophenol was completely converted into desired products
(Table 1, entries 1–5). The reaction with 2-pyridylacetylene was
found to be difficult because of the formation of a stable
Pd-alkyne intermediate (Table 1, entry 6).7 In this system,
alkynes bearing electron-rich groups were more susceptible to
undergo coupling–cyclization reaction than alkynes bearing
electron-poor groups. Even aliphatic alkynes, such as 3-butyn-
1-ol, 4-pentyn-1-ol, 1-entynyl-1-cyclohexanol and 3-cyclopentyl-
1-propyne, could give desired products 7–8 and 10–12 in high
yields (Table 1, entries 8–9, 11–13). To our knowledge, 10 and
11 were synthesized for the first time. 2-Methyl-3-butyn-2-ol
gave 9 in a low yield of 33% (Table 1, entry 10). Furthermore the
1
2
3
4
1000
9
1
95
96
87
75
1000 24 13
1000 24 14
1000 24 15
5
1000 24 16
27
6
7
1000 24 17
1000 24 18
82
31
8
1000 24 19
78
9
1000 24 20
1000 24 21
73
98
10
11
12
1000 24 22
97
1000 24
100 24
7.5b
43
23
1000
10 000
100 000 20
1000 000 40
1
9
99
499b
499b
87b
13
24
14
15
16
17
1000
1000
5
6
25
2
99
83
74
70
1000 48
1000 48
3
4
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Table 3 Synthesis of benzo[b]furans using 2-chlorophenols and alkynesa
Table 2 (continued)
2-Chloro-
Entry phenol
Time
(h)
Yield
Product (%)
2-Bromo-
Entry phenol
Time
(h)
Yield
Product (%)
Alkyne
S/C
Alkyne
S/C
1
2
3
1000 24
1
13
14
70
98
18
19
20
21
22
23
24
25
1000 48
5
—
6
29
Traceb
99
1000
2
1000 48
1000 24
1000 24
1000 24
1000 24
1000 48
100 24
Traceb
Traceb
86
1000
8
499b
63b
7
23
10 000 20
100 000 40
4
24
8
30
5
6
7
8
9
1000
1000
8
2
25
26
2
90
95
46
10
23
48
36
9
27
1000 24 10
64
1000 48
1000 48
1000 48
1000 48
1000 48
5
1000 24 11
1000 48 12
81
92
26
3
a
Conditions: 2-bromophenols 0.5 mmol, alkynes 0.6 mmol, DMF 2 mL,
Cs2CO3 1 mmol, 130 1C, [Pd(Z3-C3H5)Cl]2 2.5 ꢀ 10ꢁ4 mmol, L 5 ꢀ 10ꢁ4 10
4
b
mmol, isolated yield. GC yield.
11
6
inner alkyne 1-(phenylethynyl)-4-(trifluoromethyl)benzene was
heteroannulated with a yield of 70% (Table 1, entry 14).
Next, the reactions of various 2-bromophenols with terminal
alkynes were investigated (Table 2). 2-Bromophenols bearing
12
1000 48
1000 48
10
11
Traceb
17b
13
–CN, –CHO, –Br, –OCH3, –COOCH3, –COCH3 and –F groups all
reacted smoothly and produced desired compounds 13–15, 17,
20–22 in good to excellent yields: 73–98% (Table 2, entries 2–4,
a
Conditions: 2-chlorophenols 0.5 mmol, alkynes 0.6 mmol, DMF 2 mL,
Cs2CO3 1 mmol, 130 1C, [Pd(Z3-C3H5)Cl]2 2.5 ꢀ 10ꢁ4 mmol, L 5 ꢀ
6, 9–11). The success in the synthesis of 4-bromobenzo[b]furan
indicated that the Sonogashira coupling step site-selectively
occurred at the 2-position in accordance with the literature
b
10ꢁ4 mmol, isolated yield. GC yield.
(Table 2, entry 4).6b Due to hindrance, only 27% of 2,6- 1 h (Table 2, entry 13). To test the efficiency and longevity of the
dibromophenol was transformed into product 16 (Table 2, entry 5). catalyst, as low as 1 ꢀ 10ꢁ4 mol% of palladium was used in the
1-Bromo-2-naphthol gave the corresponding benzo[b]furan 19 reaction of 2-bromo-3-hydroxypyridine. The expected coupling
in a yield of 78%, while 4-methyl-2-bromophenol afforded product was obtained in 87% yield after 40 h and the TON was
product 18 in 31% yield (Table 2, entries 7–8). The results up to 870000, which is the best result reported in the literature.8
showed that 2-bromophenols containing electron-rich groups Substrates derived from alkynes with either electron-donating or
inhibited the reaction because the electron deficient phenoxide withdrawing groups were able to undergo an intramolecular
ion was more likely to make an attack on the triple bond cyclization reaction and generated the corresponding products
resulting in the formation of the benzo[b]furans. 2-Bromo-3- 2–5 in 29–83% yields (Table 2, entries 15–18). Good to excellent
hydroxypyridine reacted with phenylacetylene to form quickly yields of the desired products (64–92%) were obtained for
product 24 in the presence of 0.05 mol% [Pd(Z3-C3H5)Cl]2 for aliphatic alkynes (Table 2, entries 24–26).
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the complete conversion of starting 2-bromophenol. This fact is
in good agreement with the literature in which the proportion of
the cyclic compound to the acyclic intermediate in the course of
domino synthesis of benzo[b]furan increased with reaction time.9
In summary, we developed a highly efficient catalyst system
[Pd(Z3-C3H5)Cl]2–L for the one-pot systhesis of 2-substituted
benzo[b]furans from 2-halophenols and alkynes. This system
tolerates a wide range of functional groups and gives the
desired products in good to excellent yields at low catalyst
loading even if as low as 1 ppm palladium is used.
This project was supported by the National Natural Science
Foundation of China (No. 21202104).
Scheme 2 A proposed mechanism for palladium-catalyzed Sonogashira
coupling–cyclization reaction.
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6026 | Chem. Commun., 2014, 50, 6023--6026
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